Hatano Ryo, Ohnuma Kei, Otsuka Haruna, Komiya Eriko, Taki Izumi, Iwata Satoshi, Dang Nam H, Okumura Ko, Morimoto Chikao
Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan; Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan; and.
Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, Tokyo 113-8421, Japan;
J Immunol. 2015 Feb 1;194(3):960-72. doi: 10.4049/jimmunol.1402143. Epub 2014 Dec 29.
CD26 is associated with T cell signal transduction processes as a costimulatory molecule, and CD26(+) T cells have been suggested to be involved in the pathophysiology of diverse autoimmune diseases. Although the cellular and molecular mechanisms involved in CD26-mediated T cell activation have been extensively evaluated by our group and others, potential negative feedback mechanisms to regulate CD26-mediated activation still remain to be elucidated. In the present study, we examine the expression of inhibitory molecules induced via CD26-mediated costimulation. We show that coengagement of CD3 and CD26 induces preferential production of IL-10 in human CD4(+) T cells, mediated through NFAT and Raf-MEK-ERK pathways. A high level of early growth response 2 (EGR2) is also induced following CD26 costimulation, possibly via NFAT and AP-1-mediated signaling, and knockdown of EGR2 leads to decreased IL-10 production. Furthermore, CD3/CD26-stimulated CD4(+) T cells clearly suppress proliferative activity and effector cytokine production of bystander T cells in an IL-10-dependent manner. Taken together, our data suggest that robust CD26 costimulatory signaling induces preferential expression of EGR2 and IL-10 as a potential mechanism for regulating CD26-mediated activation.
CD26作为一种共刺激分子与T细胞信号转导过程相关，并且有研究表明CD26(+) T细胞参与多种自身免疫性疾病的病理生理过程。尽管我们团队和其他研究组已广泛评估了CD26介导的T细胞活化所涉及的细胞和分子机制，但调节CD26介导的活化的潜在负反馈机制仍有待阐明。在本研究中，我们检测了通过CD26介导的共刺激诱导的抑制性分子的表达。我们发现，CD3和CD26的共同作用可诱导人CD4(+) T细胞优先产生IL-10，这是通过NFAT和Raf-MEK-ERK途径介导的。CD26共刺激后还会诱导高水平的早期生长反应2（EGR2），可能是通过NFAT和AP-1介导的信号传导，敲低EGR2会导致IL-10产生减少。此外，CD3/CD26刺激的CD4(+) T细胞以IL-10依赖的方式明显抑制旁观者T细胞的增殖活性和效应细胞因子的产生。综上所述，我们的数据表明，强大的CD26共刺激信号诱导EGR2和IL-10的优先表达，这是调节CD26介导的活化的一种潜在机制。
